Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of -4.50 (-4.66, -4.24) in Cohort 1, -4.55 (-4.97, -4.13) in Cohort 2, -4.65 (-4.78, -4.17) in Cohort 3 and -4.43 (-4.81, -4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log(10) IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1-4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938-alone and in combination--were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.